A literature review of clinical and translational studies was performed to provide an overview of current concepts on regenerative treatments for spinal conditions, including platelet rich plasma and stem cell treatments to treat low back pain.
Key points
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Low back pain is a common and expensive cause of disability.
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Nonhealing annular fissures are the most common cause for low back pain.
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Early treatment of painful annular fissures may also help prevent progression to spinal deformity, stenosis, and disability.
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Intradiscal platelet rich plasma, mesenchymal stem cells, and fibrin are promising therapeutic options for intervertebral disc degeneration.
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Regenerative treatments may offer a more cost-effective solution for refractory discogenic pain and perhaps avoid expensive surgery altogether.
Introduction
Although there are many causes of low back pain, most experts agree that the beginning of the end of the spine starts with an injury to the intervertebral disc (IVD). When the disc begins to fail, the “degenerative cascade” begins and the subsequent sequelae of facet loading, spinal deformity, stenosis, and nerve root compression ensue. Adult spinal deformity is increasingly common in the aging population, with prevalence as high as 68% in adults older than 60 years. Adult spinal deformity is also a debilitating disease that greatly affects quality of life. Studies have shown that adults with scoliosis score significantly lower in self-reported outcome measures, such as the 36-item Short Form Health Survey (SF-36) questionnaire, compared with the general US population, including physical functioning, vitality, social functioning, emotional role, physical role, and mental health. Adult spinal deformity has a similar global burden as well. In fact, a prospective multicenter international database including 8 industrialized countries found that patients with adult spinal deformity actually have lower health-related quality of life scores when compared with patients with common chronic conditions. such as self-reported arthritis, chronic lung disease, congestive heart failure, and diabetes.
The rising health care costs, the physical impact, and functional decline related to adult spinal deformity engender a need for more preventive measures and cost-effective treatments, such as preventive and regenerative interventions. Despite spending billions of dollars in various treatments, both surgical and nonsurgical current treatments have failed to meet patient expectations and curb the ever-escalating health care costs related to managing this condition. The concepts of cutting out discs, fusing the spine, burning disc nerve endings, and injecting steroids around inflamed structures all fail to address the underlying pathophysiology and do little to change the natural history of disc degeneration. It is our opinion that we need to be less aggressive with our surgical treatment of the spine, and more aggressive with intervening earlier in the disease process with regenerative treatments. Hopefully this approach will not only lead to better patient outcomes, but also to a more sustainable, cost-efficient way to manage this significant societal burden. In this article, we focus our review on the current literature that exists regarding the clinical and translational studies on regenerative treatments for healing the IVD.
Introduction
Although there are many causes of low back pain, most experts agree that the beginning of the end of the spine starts with an injury to the intervertebral disc (IVD). When the disc begins to fail, the “degenerative cascade” begins and the subsequent sequelae of facet loading, spinal deformity, stenosis, and nerve root compression ensue. Adult spinal deformity is increasingly common in the aging population, with prevalence as high as 68% in adults older than 60 years. Adult spinal deformity is also a debilitating disease that greatly affects quality of life. Studies have shown that adults with scoliosis score significantly lower in self-reported outcome measures, such as the 36-item Short Form Health Survey (SF-36) questionnaire, compared with the general US population, including physical functioning, vitality, social functioning, emotional role, physical role, and mental health. Adult spinal deformity has a similar global burden as well. In fact, a prospective multicenter international database including 8 industrialized countries found that patients with adult spinal deformity actually have lower health-related quality of life scores when compared with patients with common chronic conditions. such as self-reported arthritis, chronic lung disease, congestive heart failure, and diabetes.
The rising health care costs, the physical impact, and functional decline related to adult spinal deformity engender a need for more preventive measures and cost-effective treatments, such as preventive and regenerative interventions. Despite spending billions of dollars in various treatments, both surgical and nonsurgical current treatments have failed to meet patient expectations and curb the ever-escalating health care costs related to managing this condition. The concepts of cutting out discs, fusing the spine, burning disc nerve endings, and injecting steroids around inflamed structures all fail to address the underlying pathophysiology and do little to change the natural history of disc degeneration. It is our opinion that we need to be less aggressive with our surgical treatment of the spine, and more aggressive with intervening earlier in the disease process with regenerative treatments. Hopefully this approach will not only lead to better patient outcomes, but also to a more sustainable, cost-efficient way to manage this significant societal burden. In this article, we focus our review on the current literature that exists regarding the clinical and translational studies on regenerative treatments for healing the IVD.
Discogenic pain
The IVD is composed of a central nucleus pulposus, consisting of hydrophilic proteoglycan and type II collagen, and the outer annulus fibrosus, made of a fibrous ring of mostly type I collagen. Due its intrinsic hydrostatic pressure, the nucleus pulposus can bear heavy compressive loads, whereas the annulus fibrosus resists heavy tensile stresses. Biomechanical studies have shown that torsion and flexion contribute to degenerative changes in the lumbar discs. Disc herniations can be due to progressive degenerative changes from repetitive stress, or acute in nature due to trauma. With repetitive stress, the annulus fibrosus fibers swell and disrupt as the annulus fibrosus undergoes myxomatous degeneration and cyst formation. At the same time, the nucleus pulposus dehydrates, turns fibrotic, and eventually undergoes necrosis and herniation. The nucleus pulposus can herniate through annular fissures or endplate disruptions. The adult IVD is the largest avascular structure in the human body and relies on passive diffusion from adjacent endplate vessels for nutrition, resulting in poor inherent healing potential. In fact, only 3% of disc bulges and 38% of focal protrusions resolve spontaneously. Broad-based disc protrusions, extrusions, and sequestrations have a better prognosis, with approximately 75% to 100% resolving spontaneously.
Nonhealing annular fissures of the IVD have been implicated as one of the major causes for chronic low back pain. A concomitant upregulation of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis (TNF) alpha, leads to chemical sensitization of the rich network of nerve fibers that supply the outer annulus fibrosus, resulting in pain with normal activities of daily living. As the degenerated disc cells upregulate IL-1 expression, the native disc cells also increase matrix degrading enzyme production expression. TNF-alpha expression from the degenerated tissue also upregulates matrix degrading enzymes and stimulates nerve ingrowth. Furthermore, annular fissures may also contribute to a chemical radiculitis due to the release of inflammatory mediators into the epidural space. As the IVDs degenerate, there is loss of disc space height, and subsequent loading onto the posterior elements. When the disc degenerates asymmetrically, spinal deformity and stenosis ensue.
Considering the pathophysiology of disc degeneration, regenerative treatments need to focus on either stimulating production of extracellular matrix, or inhibiting the cytokines that upregulate matrix degrading enzymes. In turn, as the regenerative treatments slow down or reverse disc degeneration, the subsequent loss of disc space height, increased loading on posterior elements, and spinal stenosis also may be prevented.
Platelet rich plasma
The solution for IVD regeneration and inhibition of matrix degrading enzymes may be found in platelet rich plasma (PRP). PRP is acquired from an autologous sample of blood that is centrifuged to increase the platelet concentration up to 3 to 8 times the normal concentration in whole blood. At the same time, PRP also contains amplified levels of growth factors and cytokines, which stimulate tissue healing. The alpha granules in platelets also secrete growth factors that are essential for tissue repair, such as basic fibroblast growth factor (b-FGF), epithelial growth factor, insulinlike growth factor (IGF-1), platelet-derived growth factor, and vascular endothelial growth factor. The growth factors also increase collagen content, promote endothelial regeneration, and stimulate angiogenesis.
Intradiscal platelet rich plasma
Intradiscal Platelet Rich Plasma: In Vitro and In Vivo Studies
Clinicians have hypothesized that placing a high concentration of growth factors, such as in PRP, directly at the site of collagen injury can allow the growth factors to act as humoral mediators to induce the natural healing cascade ( Box 1 ). An in vitro study of PRP-infused human IVD cultures supports this hypothesis and exhibited nucleus pulposus proliferation and differentiation as well as upregulated proteoglycan synthesis. Animal models of experimentally injured IVD treated with intradiscal PRP have also demonstrated restoration of normal cellular architecture and disc height. Furthermore, PRP may also have an anti-inflammatory effect. An in vitro study found that cytokine (TNF-alpha and IL-1) induced proinflammatory degrading enzymes and mediators were suppressed with the addition of PRP into the collagen matrix of human nucleus pulposus cells. A rabbit model with degenerated IVDs injected intradiscally with PRP-impregnated gelatin hydrogel microspheres resulted in significantly higher water content determined by MRI, which corresponded with increased intradiscal proteoglycan content, upregulated mRNA precursors for type II collagen, and significantly reduced apoptotic nucleus pulposus cells. Similarly, in a percutaneous annulus puncture-induced degenerated disc rat model, discs treated with PRP had fewer inflammatory cells, higher preservation of normal morphology, and higher fluid content in T2 MRI compared with sham at 4 weeks postinjection.
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Increased platelet concentrations 3 to 10 times over whole blood
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Platelets secrete growth factors (basic fibroblast growth factor, epithelial growth factor, insulinlike growth factor-1, platelet-derived growth factor, vascular endothelial growth factor)
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Increase collagen content
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Endothelial regeneration
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Stimulate angiogenesis
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Suppress proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-1)
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Reduce apoptosis
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Concentrated fibrinogen content
Intradiscal Platelet Rich Plasma: Clinical Studies
A recent double-blind randomized control trial (RCT) involving intradiscal PRP injections of patients with chronic moderate to severe lumbar discogenic pain, has demonstrated improvement in functional and pain scores. This study involved 47 participants randomized to receive a single injection of autologous PRP (29 in the treatment group) or contrast agent alone (18 in the control group) into symptomatic degenerative IVDs. The patients included were those with low back pain persisting for at least 6 months and refractory to conservative treatment, including oral medications, rehabilitation therapy, and/or injection therapy ( Box 2 ). Before the intradiscal PRP procedure, a caudal epidural injection was trialed to determine if the patient with presumed discogenic low back pain would receive therapeutic benefit from the caudal injection. A prospective cohort study has shown that patients with at least 3 months of axial low back pain associated with central disc protrusions at L4–5 and/or L5–S1 do experience improvements in pain, function, and satisfaction after receiving caudal epidural steroid injections (Lee J, Nguyen E, Harrison J, et al. Fluoroscopically guided caudal epidural steroid injections for axial low back pain as a result of central disc protrusions: a prospective outcome study. Pain Med. Submitted for publication). The subjects who had relief of low back pain after the caudal injection then were considered for inclusion in the intradiscal PRP randomized control study.
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Low back pain greater than 6 months
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Failed conservative treatment : oral medications, physical therapy, injections
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Transient relief following caudal epidural steroid injection
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MRI : disc heights of at least 50% of normal, disc protrusion <5 mm
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Provocative discography : grade 3 or 4 annular fissures and <2 mL filling of contrast into annular fissure
Furthermore, there was strict selection criteria for included IVDs. Only the IVD heights of at least 50% of normal and with disc protrusion less than 5 mm on MRI or computerized tomography were included in the study. Disc extrusions, sequestered discs, and spinal stenosis at the levels investigated were excluded. The symptomatic discs were found via provocative discography performed on the day of the intradiscal PRP injection. Only grade 3 or 4 annular fissures as determined by discography were included. At 8 weeks, the intradiscal control (contrast only) group was allowed to cross over to receive intradiscal PRP if they failed to show improvement.
At 8 weeks, there were statistically significant improvements in pain (Numeric Rating Scale [NRS] for best pain), function (Functional Rating Index [FRI]), and patient satisfaction (North American Spine Society Outcome Questionnaire) in the intradiscal PRP group as compared with the control groups. In addition to the RCT, a longitudinal analysis of the intradiscal PRP treatment group at 6 months, 1 year, and 2 years was conducted. This revealed continued improvement in the NRS best pain, FRI function, and SF-36, and clinically significant improvement sustained at 2 years postinjection for NRS worst pain, FRI function, SF-36 pain and function (reference both of our articles here). No adverse events of neurologic injury, progressive disc herniation, or disc space infection occurred throughout the course of the study.
The investigators concluded that PRP is a safe and sustainable treatment option for lumbar discogenic pain. This study demonstrated improved functional outcomes after intradiscal PRP, but the regenerative properties of PRP in the IVD is still inferred. The next step in our research will be a prospective cohort study of intradiscal PRP that will include sequential MRI of the spine to ascertain improvements in disc space height, healing of high-intensity zones (HIZs), resorption of focal protrusions, and possible improvement in Pfirrmann scores. A case report with the same investigators demonstrated positive increased T2 nuclear signal intensity on MRI of IVD 1 year after intradiscal PRP injections, which correlated with improvement in the patient’s low back pain and ability to return to running ( Fig. 1 ) (JR Harrison, RJ Herzog, GE Lutz. Increased nuclear T2 signal intensity following intradiscal platelet rich plasma: a case report, Submitted to PM&R).
The investigators in this randomized control study described their technique for intradiscal PRP injection with 1 to 2 mL of autologous PRP and a double-needle extrapedicular technique, immediately after contrast administration for discography ( Box 3 ). The patient is positioned prone on the fluoroscopy table after receiving 1 g cephazolin at 30 minutes before the procedure. After sterile preparation and local anesthesia, a 25-gauge needle is advanced through a 20-gauge needle introducer into the midportion of the suspected disc levels using anteroposterior and lateral fluoroscopic imaging to confirm proper needle positioning. Thereafter, 1 to 2 mL of contrast agent is injected into the disc and the participant endorses concordant or discordant pain reproduction of low back pain. Only the discs that produce concordant pain and exhibit the contrast filling an annular fissure with incomplete annular disruption (<2 mL) are injected with PRP. No extension tubing is used during the injection. If more than one disc reproduces concordant pain, then the 3 to 4 mL of PRP obtained is divided into each of the affected discs.
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1 g intravenous cephazolin 30 minutes before injection
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Local anesthesia with consideration of intravenous sedation
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Double-needle technique (20-gauge needle introducer and 25-gauge needle) via extrapedicular technique ( Fig. 2 )
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1 to 2 mL contrast injected intradiscally to confirm concordant low back pain; and contrast filling of annular fissure (<2 mL)
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PRP 1 to 2 mL injected intradiscally slowly over 2 to 3 minutes
